Epilepsy is one of the most common chronic neurological disorders. The disease is characterized by recurrent seizures, which originate from abnormal and excessive activity of cerebral neurons and result in a paroxysmal disorganization of brain function. Types of epilepsy include partial (symptomatic) and generalized idiopathic seizures. Partial epilepsy is “localization related” and originates in a limited area of the brain. The generalized form of epilepsy is not caused by a specific brain lesion or disease, other than a possible genetic propensity to generate seizures. Generalized, or grand mal, seizures include tonic-clonic seizures, in which the entire body undergoes convulsions. Left untreated, epilepsy can degenerate into status epilepticus, a potentially fatal neurological emergency [Antiepileptic Drugs; eds. R. H. Levy, R. H. Mattson and B. S. Meidrum; 4th Edition, Raven Press, NY, N.Y.; Aicardi. Epilepsy in children. 2nd edition. New York: Raven Press, 1994: 18-43]. Idiopathic epilepsy appears to be a heritable disorder though little is known about the precise genetic or biochemical defects involved (Andermann In Genetic Basis of the Epilepsies, eds. Anderson V E, Hauser W A, Penry J K, Sing C F. New York: Raven Press 1982: 355-74; Anderson E V, Hauser W A. Genetics. In: Dam M, Gram L, ed. Comprehensive Epileptology. New York: Raven Press 1990:57-76). Recent research has indicated the possibility of genetic predisposition to the development of localization-related epilepsy, in particular post-traumatic epilepsy. In this type of epilepsy, a head injury is the resolving exogenous factor inducing the disease with a low penetration of the pathological hereditary factor.
Over 53 million people worldwide suffer from epilepsy, with 2.5 million who have had, or who will have seizures at some point in the U.S. alone. Epilepsy primarily affects children and young adults. Almost 50% of new epilepsy cases occur prior to age 25. About 28% of epileptic patients have intractable epilepsy that is resistant to antiepileptic treatment. A wide spectrum of antiepileptic drugs is used for epilepsy treatment [Antiepileptic Drugs; eds. R. H. Levy, R. H. Mattson and B. S. Meldrum; 4th Edition, Raven Press, NY, N.Y.; Aicardi, Epilepsy in children, 2d Edition, Raven Press, 1994]. Nevertheless, a goal, that was expressed 10 years ago (Drugs and Market Development, 1992, v.2, N3), namely to develop antiepileptic drugs (AEDs) which are equally effective yet less toxic than the AEDs currently on the market, has not been accomplished.
One specific form of epilepsy, known as “pyridoxine-dependent epilepsy” has been described as a rare (1:100 000) autosomal recessive genetic disorder that causes severe convulsions with subsequent mental retardation in neonates and infants (Hunt et al. Pediatrics 1954; 13:140; Rosenberg In: Medical Genetics McKusic V A, ed. 1995: 73-8; Shideler Am. J. Med. Technol. 1983; 49:17-22 ; Scriver and Hutchison Pediatrics 1963; 31:240-50).
It was reported in the art that pyridoxine-dependent epilepsy can be treated by administration of pyridoxine (Aicardi, Epilepsy in children, 2d Edition, Raven Press 1994; Epilepsy Problems Solving in Clinical Practice; eds. D. Schmidt, S. C. Schachter; Martin Dunitz, 2000). The literature, however, suggests that medicinal method of treating pyridoxine-dependent epilepsy is unsuitable for the treatment of other forms of epilepsy.
Vitamin B6 (pyridoxine) plays a crucial role in the metabolism of amino acids, proteins, carbohydrates, lipids, hormones and neuromediators (Lumeng L, Li T K. Mammalian vitamin B6 metabolism: regulatory role of protein-binding and the hydrolysis of pyridoxine 5′-Phosphate in storage and transport. In: G. P. Tryfiates, ed. Vitamin B6, Metabolism and Role in Growth. Food & Nutrition Press, Inc., Westport, Conn. 06880 USA, 1980: 27-51). The active form, pyridoxal-5′-phosphate (PLP), is the coenzyme of a large number of enzymes in mammalian tissues, including transaminases, decarboxylases and lyases, etc. Neurotransmitters (e.g. dopamine, norepinephrine, serotonin, tyramine, tryptamine, taurine, GABA (γ-aminobutyric acid), and indirectly acetylcholine) are also synthesized and/or metabolized by PLP-dependant enzymatic reactions (for reviews:Metzler, Biochemistry, Academic Press, 1977; Ebadi M., Regulation and function of pyridoxine phosphate in CNS. Neurochem.Int 1981, 3, 181-206; Leklem 1988 Vitamin B6 metabolism and function in humans. In: Clinical and physiological Application of vitamin B6 (Leklem & Reynolds eds.,) Alan R. Liss, NY, 1988; Shideler Ch. Vitamin B6: An Overview. Am. J. Med. Technol. 1983; 49:17-22).